The biologic effects of substance abuse, in particular the effects on the immune system, may significantly contribute to the neuropathogenesis of HIV infection. Opioids and substance P (SP) modulate immune function and may affect HIV infection of immune cells. The overall goal of this investigation is to understand the mechanisms of interaction of opioids and SP in the immunopathogenesis of HIV infection in human immune cell s. Our hypothesis is that opioids affect HIV infection of immune cells by affecting neuropeptides, such as SP. We have demonstrated that SP modulates mononuclear phagocyte function and affects HIV infection n in vitro. In addition, we have recently demonstrated that monocytes and lymphocytes express SP and its receptor (Ho et al., J. Immunol. 1997, Lai et al., J. Neuroimmunol, 1998). Furthermore, our preliminary in vitro experiments demonstrate that morphine enhances SP gene expression and stimulates SP production in human monocytes/macrophages. In this investigation, we will address four specific aims: First, we will determine whether opioids affect expression of SP and its receptor in human immune cells (microglia, monocytes/macrophages, and lymphocytes). Second, we will determine whether opioids and/or SP affect expression of HIV receptors (CD4, CCR3, CCR-5, and CXCR4) and production of beta chemokines (Rantes, MIP-1 a, b) in these immune cells. Third, we will determine whether interaction of morphine (or other opioid receptor agonists) and SP modulates HIV replication, and whether specific antagonists for different opioid receptors or SP receptors play a role in blocking HIV infection of monocytes/macrophage (including microglia) and lymphocytes. And finally, we will determine SP levels in peripheral blood samples from HIV positive and HIV negative individuals who are currently receiving methadone maintenance treatment, as well as HIV+ and HIV- controls. The results of these studies should advance our understanding of opioids and SP as cofactors in the immunopathogenesis of HIV infection of drug abusers. These studies may also provide clues toward development of therapeutic strategies for HIV infection and AIDS.